| BackgroundThe incidence of adverse drug reactions of Qingkailing injection is less in large sample analysis;and the characteristics of adverse events/reactions of Qin gkailing injection which through case reports,literature evaluation,Hospital Infor mation System(HIS),Spontaneous Report System(SRS)and so on,are basically consistent with the recording of<Pharmacopoeia of the People's Republic of C hina>;Risk factors that affect the occurrence of adverse drug reactions in Qingk ailing injection,in addition to the types of drugs that have been confirmed for combined use,after through the analysis of literature evaluation and HIS,it is also believed that patients have Hepatic Sclerosis or Electrolyte Disturbance,Uri nary Infection,Neuromuscular system and other diseases,allergy history,Hyperind ication(acute tonsillitis,High Blood Pressure,etc.),Solvent situations(the instructio ns not mentioned that are allowed to be mixed with Glucose and Sodium Chlo ride),Combination therapy(Adenosine,Nifedipine,Insulin,Vitamin C,etc.)affect the occurrence of adverse drug reactions in Qingkailing injection.The evaluation of adverse drug reactions is a re-evaluation of the drug aft er it is marketed,which can correctly and comprehensively understand the safe ty of the drug,mainly through passive and active monitoring of the severity le vel of the drug safety report.According to the literature summary,the data minin g methods used for the evaluation of adverse drug reactions are:Disproportional ity measures,Chi-square test and Logistic regression method,etc.Logistic regressi on controls the confounding factors,estimates the relative risk of influencing fa ctors,and establishes a regression model for the target adverse reactions,taking the other as a control,but at the same time ignoring the severity levels of ea ch report table,applied to the detection of single drug's adverse reaction signals,has a good effect;The advantage of the random forest method is that there is basically no limit to the size of the data set,the method of inline missing fil ling,no overfitting and collinearity,etc.,with ariable importance score to objectiv ely evaluate the risk factors that affect the occurrence of adverse reactions.The result of practical value is that it is possible to analyze the variable importan ce score of each factor-adverse reaction combination,and to explore the associat ion between each variable and the specific adverse reaction symptoms combine d with the original case data.In order to fully understand the incidence,characteristics of ADR and risk factors of Qingkailing injection in the real world,this study used multi-center,no n-control,drug-oriented prospective hospital centralized monitoring for analysis.Objective(1)The objective of main research:To investigate the safety of Qingkailin g injection in large-scale population after marketing,identify and judge the inci dence,nature,characteristics and risk factors of adverse drug events/reactions.(2)The objective of secondary research:To explore the methods to explor e the factors affecting the occurrence of adverse drug reactions in Traditional Chinese Medicine injection,and to provide technical reference for monitoring t he clinical adverse reactions after the TCM injection ismarketed.Methods(1)Research Design:Adopting the multi-center,non-control,drug-oriented pr ospective hospital centralized monitoring.(2)Monitoring Object:According to the hospital centralized monitoring progr am of Qingkailing Injection Adverse Drug Reaction,the unit of project design i s the Institute of Clinical Basic Medicine,China Academy of Chinese Medical Sciences.During the period from January 2013 to March 2016,30,842 patients who used Qingkailing injection were treated at Shenzhen Ren'ai Hospital,Qing he County Traditional Chinese Medicine Hospital,and Yuanyang County People's Hospital,etc.,48 medical institutions in total.(3)Monitoring Method:Patients who use this formulation are included indisc riminately.According to the standards for reporting intensive hospital monitoring of Traditional Chinese Patent Medicines,develop a unified monitoring plan,mon itoring specifications,set up a research group,a supervision group,conduct in-dept h clinical observation,and follow up the patient's medication response,and the cl inicians/nurses/pharmacists complete the forms of observation based on the med ical records and actual observations(4)Data Processing:General Coordinator verifies all watchlists,the original m aterials are kept by the Institute of Clinical Basic Medicine,China Academy of Chinese Medical Sciences.With reference to the internationally used WesternMedical Diagnostic Standards for the<International Statistical Classification ofDiseases and Related Health Problems>(ICD-10),standardize diagnostic names;sta ndardize the diagnosis and syndrome of TCM with reference to<Traditional C hinese Medicine>;the names of adverse drug reactions in ADR cases were stan dardized with reference to the dictionary of Meddra.(5)Quality Control:Quality control is mainly implemented from the folio win g 7 aspects:monitoring center,monitoring staff,monitoring progress,original docu ments,electronic data,archive management,quality management,and the original d ocuments and electronic data are important elements very much.(6)Statistical Analysis:The data processing and statistical work were comple ted by professionals who were not involved in the design of the scheme by th e Institute of Clinical Basic Medicine,China Academy of Chinese Medical Sci ences.Analysis the characteristics of adverse drug reactions of Qingkailing injecti on:The statistical analysis software version 3.5.0 of the R is used for statistical calculation and programming.For counting data,using the description method to analyze the frequency and percentage;for measurement data,the frequency and percentage are described in segment description.Analysis the influencing factors of adverse drug reactions in Qingkailing i njection using nested case-control:?Using the study of nested case-control,follo wing 1:3 pairing approach,form ADR and control group.Statistical tests were pe rformed using a two-side test,and a preliminary screening of suspicious risk fac tors with P?0.2,the confidence interval uses confidence of 95%.?Based on the results of descriptive preliminary analysis,it was included in the univariate an alysis and significant factors(P?0.2)were included in the Logistic multivariate regression for analysis.When.P?0.05 and the estimated coefficient is positive,t he factor is considered to be a risk factor for the occurrence of ADR;When P?0.05 and the estimated coefficient is negative,the factor is considered to be a non-risk factor for the occurrence of ADR.?Using package.RandomForest in R software,a total of 368 cases in the ADR and control group were divided into 256 training sets by 7:3 cross-training to establish a Random Forest model,an d a test set of 112 cases was used to test the prediction effect.Based on the results of descriptive preliminary analysis,66 variables were included to constru ct the influencing factors of Random Forest model,according to the MeanDecr easeGini index,we analyzed the total importance score of each factor and the variable importance score of each factor-adverse reaction symptom to explore t he risk factors affecting the occurrence of adverse reactions.Results(1)Monitoring the general situation of patients with Qingkailing injection:A dopting a prospective hospital Centralized monitoring of multi-center,non-control,drug-oriented for 30,842 patients using Qingkailing Injection,there were 16209 males(52.55%)and 14633 females(47.45%),and it is distributed in all ages,18 and 30 years old is 5691 patients;Among the patients,western medical diagn osis involves various disease systems,mainly are infections and infectious diseas es such as Respiratory infections(11624 cases),Bronchitis(5593 cases),and Pharyn gitis(2788 cases),the diagnosis of TCM is mainly fever heat to close the lungs(3863 cases),heat poison(2289 cases),and heat-resistance syndrome(1521 cases),et(2)Incidence and characteristics of ADR in Qingkailing injection:Of the 30,842 patients who used Qingkailing injection,92 occured ADR,the incidence of ADR is 3‰;Involving the skin and subcutaneous tissues,systemic diseases and various reactions at the site of administration,gastrointestinal system,various ner vous systems,heart organs and so on,the main manifestations are(Frequency?10 cases):rash(42 cases),itching(32 cases),nausea(16 cases),chest tightness(15 case s),dizziness(14 cases),vomiting(12 cases),etc.(3)Descriptive analysis of ADR of Qingkailing injection in Nested Case-co ntrol research:Descriptive analysis of ADR and control group in 368 cases of n ested cases using Qingkailing injection,a statistically significant level P?0.2 is the following:previous medical history(Lung Cancer,Hyperlipidemia,gastritis,etc.);Previous allergy history(P=0.1);History of ADR(P=0.052),History of ADR_rash(P=0.004);Western medicine diagnosed(Cerebral insufficiency,Pneumonia,Urinary tract infection,etc.);The diagnosis of TCM(Liver dampness and heat syndrome,Fever heat to close the lungs,Heat-resistance syndrome,etc.);Vehicle dose(P=0.063),Interval medication's time(P-0.036);Combine other drug types(P=0.114);Conco mitant medications(Oxiracetam injection,Pioglitazone Hydrochloride tablets,lopam idol injection,Dioxopromethazine Hydrochloride tablets,Ethylenediamine Diacetura te injection,Compound Aluminium Hydroxide tablets,etc.);The combined drug sy stem(OTC cold medication,OTC respiratory medicine,metabolic and endocrine sy stem drugs,etc.);The combined drug pharmacological effect(allergic mediator,anti pyretic analgesics,antihypertensive drugs,etc.).(4)Analysis of risk factors that affecting ADR in Qingkailing injection bas ed on Logistic Regression:Based on descriptive analysis of the ADR in the nes ted case-control research(statistically significant P?0.2),66 suspicious factors s uch as the PMH of lung cancer related to the occurrence of ADR in Qingkaili ng injection,were screened for Logistic regression analysis,the risk factors consi dered to be related to the occurrence of ADR in Qingkailing injection are:histo ry of Tumor,ADR history of Rash,currently suffering from Gastritis and Stroke;the risk of ADR in combination of Qingkailing injection and Traditional Chine se Medicine is not obvious.(5)Analysis of risk factors affecting ADR in Qingkailing injection based o n Random Forest model:Adopting Random Forest model and ending with ADR,based on the results of descriptive preliminary analysis,66 variables were includ ed to construct Random Forest model and 100 decision trees were constructed randomly,and the accuracy of the random forest model is 78%,and the predictio n model is good.According to the overall score of variable importance,the top 6 of MeanDecreaseGini is:ADR history of Rash,history of Tumor,currently suff ering from Cerebral Insufficiency,Previous allergy history,combined with TCM,c urrently suffering from Gastritis,etc.Adopting Random Forest model and ending with preferred language code f or the names of ADR(rash,itching,nausea,chest tightness,dizziness,vomiting),relate d factors of ADR in Qingkailing injection(ADR history of Rash,history of Tum or,currently suffering from Cerebral Insufficiency,Previous allergy history,Combin ed with TCM,currently suffering from Gastritis)as explanatory variables,we thin k that when using the Qingkailing injection:patients had ADR history of Rash caused by itching,rash importance score significantly higher than nausea,chest tightness,dizziness,vomiting;the importance of nausea and chest tightness cau sed by the history of tumor was significantly higher than that of rash,itching,dizziness and vomiting;the importance score of chest tightness,nausea and diz ziness caused by Cerebral Insufficiency was higher than that of rash,itching a nd vomiting;the importance score of rash and itching caused by previous allerg ic history was significantly higher than that of nausea,chest tightness,dizzines s and vomiting;the importance score of rash,itching and nausea caused by co mbination with TCM was significantly higher than that of chest tightness,dizzi ness and vomiting;the importance of rash and itching caused by Gastritis was s ignificantly higher than that of nausea,chest tightness,dizziness and vomiting.Conclusions(1)30,842 patients using Qingkailing injection,92 occured ADR,the inciden ce of ADR is 3‰,is occasional adverse reactions;Involving the skin and subcut aneous tissues,systemic diseases and various reactions at the site of administra tion,gastrointestinal system,various nervous systems,heart organs and so on,the main manifestations are:rash,itching,nausea,chest tightness,dizziness,vomiting,etc(2)The risk factors associated with ADR of Qingkailing injection are:histor y of Tumor,Previous allergy history,ADR history of Rash,currently suffering fro m Gastritis,Cerebral Insufficiency and Stroke.(3)Used Qingkailing injection,patients had history of Tumor can easily caus e ADR of nausea,chest tightness;patients had Previous allergy history,ADR histo ry of Rash and Gastritis can easily cause ADR of itching and rash;patients are currently suffering from Cerebral Insufficiency,can easily cause ADR of chest tightness,nausea,dizziness.(4)At present,the clinical use of Qingkailing injection is relatively standar dized,however,patients with Cerebral Insufficiency and Stroke should pay clos e attention to the reaction of Qingkailing injection(chest tightness,nausea,dizz iness,etc.)and stop using it immediately if any;patients with Gastritis are advi sed that used Qingkailing injection cautiously. |
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